Oxadiazolopyrimidines and method of preparing the same



Patented Dec. 19, 1950 UN 1] TED S TAT-ES PATENT OFFICE 2,534,897OXADIAZOLOPYRIMIDINES AND; METHOD OF PREPARING THE SAME JamesBoothePearl River, and Coy W. Waller,

Nanuet, N. Y., assignors to American Cyanamid Company, New York, N. Y.,a corporation of Maine 6 Claims.

This invention relates to new organic compounds. More particularly, itrelates to ox'adiazolopyrimidines and methods of preparing the same.

The compounds of the present invention may be illustrated by thefollowing structural formula:

in which R is a member of the group consisting of hydroxyl and aminoradicals.

The compounds of the present invention are white solids somewhat solublein water but soluble to a greater extent in alkaline aqueoussolutions.They decompose at high temperatures, usually without melting.

The compounds of the present invention may be prepared by reacting4-hydroxy-5-aminopyrimidines or salt thereof with nitrous acid in asolvent. The preferred solvent is water although mixtures of water andsmall amounts of water miscible solvents, such as ethanol, may be used.

The intermediates used in the .present invention, such as2,5-diamino-4,6-dihydroxypyrimidine and2,4,6-trihydroxy--aminopyrimidine, are known compounds and can beprepared by methods described in the chemical literature.

In carrying out our invention nitrous acid is used to form the-oxadiaz'olo ring with the 4-hydroxy-5-aminopyrimidine. The nitrous acidmay be added directly to the reaction mixture, however, it is usuallymore desirable to form the nitrous acid within the reaction mixture bythe action of an acid such as acetic, nitric, hydrochloric, sulfuric,etc. on alkali or alkaline earth nitrites such as sodium nitrite andpotassium nitrite. Organic nitrites such as ethyl nitrite and amylnitrite can be used although they are generally more expensive and lessdesirable.

The reaction to prepare the compounds takes place readily attemperatures between about 0 C. and 100 C. A convenient method ofconducting the reaction is to mix the reactants in a suitable solvent atroom temperature or below and after allowing the reaction to proceed ashort time, it is completed by a short period of heating on a steambath.

The product may be isolated from the reaction mixture as an insolubleprecipitate by chilling the mixture. The product can be further puri- 2'fied by dissolving in an alkaline solution and precipit'atin'g theproduct by decreasing the pH to about 1.

The product, '5,7-'dihydroxy(3,l,2)oxadiazolo- 4,5-dJpyrimidine, canalso be prepared from 5 amino "7hydroxy(3,1,2)oxadiazolo-[4,5-dlpyrimidine by heating in a mineral acidsolution with or without the presence of an alkali metal nitrite. Bythis method the 5-amino group is converted into a hydroxyl radical.

The compounds of the present invention are antagonistic toward guanineand inhibit the growth of micro-organisms which require guamine as agrowth factor. They also have been found to have an effect on neoplasms.

The invention will now be illustrated in greater particularity by meansof the following specific examples showing the preparation ofillustrative oxadiazolopyrimidines from the corresponding4-hydroxy-5-aminopyrimidines.

Example 1 5 N hydrochloric acid. It was cooled and 0.75

g. of sodium nitrite was added dissolved in water. The pyrimidine didnot quite all go in-solution so a little more sodium nitrite was added.The solution was filtered and left at room temperature for two hours. Itwas then warmed on a steam bath thirty minutes and brought to a boil.The solution was cooled and ammonium hydroxide was added to about pH l.The white precipitate was dissolved in dilute sodium hydroxide, treatedwith activated charcoal, precipitated with acetic acid, centrifuged,washed well with water, alcohol and ether, and dried. O-n analysis forcarbon, hydrogen and nitrogen the values obtained agreed very closelywith the theoretical values for 5-amin0- 7 hydroxy (3,1,2)-oxadiazo1o[4,5-d] -pyrimidine.

Example 2 One hundred and twenty-five grams of2,5-diamino-4,6-dihydroxypyrimidine sulfate was dissolved in liters ofcold water with 200 cc. of 10 N sodium hydroxide solution. Eighty gramsof sodium nitrite was then added. The resulting solution was stirredvigorously and maintained at 5 C'. to 10 C. while 500 cc. ofconcentrated hydrochloric acid was added dropwise through a long stemfunnel. The stem of the funnel was immersed in the reaction solution.The mixture was stirred for one hour at 10 (3., one at 20 0., and onehour at C., and heated to C. and cooled overnight in the chill room. Theproduct,

Example 3 To a slurry of 3 grams of 2,4,6-trihydroXy-5- aminopyrimidine15 cc. of concentrated hydrochloric acid and 50 cc. of water at 5 C. wasadded a solution of three grams of sodium nitrite in 15 cc. of waterdropwise through a dropper funnel with vigorous stirring and cooling tomaintain a temperature of C. to 10 C. The solution was stirred for onehour while it warmed to room temperature; then stirred for one hour at50 C. where solution was complete. The clear solution was filtered andcooled to C. The product, 5,7 dihydroxy- (3,1,2) -oxadiazolo [4.5-6.1-pyrimidine, was collected, washed, and dried; Weight 0.3 gram,decomposition point 270-275 C.

A second crop was obtained by concentrating the above filtrate todryness, extracting the residue with hot (90 C.) 100 cc. methylCellosolve, evaporating oi? the methyl Cellosolve under vacuum andcrystaliizing the resulting residue from cc. of water. This second cropwas recrystallized irom 10 cc. of water a second time; yield, 0.3 gram.

Example 4 To a solution of 5.5 grams of 5-amino-7-l1ydroxy (3,1,2)-oXadiazolo[4,5-dl pyrimidine in 150 cc. of 20% sulfuric acid at 9G-95C. was added dropwise a solution of 27 .5 grams of sodium nitrite in 75cc. of water over a period of 2 hours while heating on a steam bath andmaintaining a temperature of -95 C. by heating on a steam bath withvigorous stirring using a me- 'hour period maintaining the aboveconditions was necessary to complete the reaction. The re sultingsolution was cooled at 5 C. overnight and filtered. The product wasrecrystallized from cc. of water; yield 3.5 g. This product had 4 thesame ultraviolet absorption and decomposi tion point as the material inExample 3.

Example 5 A mixture of 5 g. of 5-amino-"I-hydroxy- (3,1,2)oxadiazolo[4,5-dl-pyrimidine, 15 cc. of concentrated sulfuric acid (sp.gr. 1.84) and 100 cc. of water was heated to refluxing for 4%.; hours.The mixture was filtered and the filtrate cooled. The crystals of 5,7dihydroxy (3,1,2) oxadiazolo- [4,5-dl-pyrimidine were collected, washedand dried; weight 3.4 grams.

We claim:

1. Chemical compounds having the general formula:

in which R is a member of the group consisting of hydroxyl and aminoradicals.

2. 5 amino '7 hydroxy (3,1,2) -oxadiazolo- [4,5-d] -pyrimidine.

3. 5,7 dihydroxy (3,1,2) oxadiazolo[4,5-dlpyrimidine.

4. A method of preparing chemical compounds corresponding to the generalformula:

in which R is a member of the group consisting of hydroxyl and aminoradicals which comprises mixing together a compound of the groupconsisting of 2,5-diamino-4,6-dihydroxypyrimidine, 2,4,6 trihydroxy 5aminopyrimidine and salts thereof with nitrous acid in a solvent.

5. A method of preparing 5-amino-7-hydroxy- (3,1,2)-oxadiazolo[4,5-dlpyrimidine which comprises mixing together2,5-diamino-4,6-dihy droxypyrimidine sulfate and nitrous acid in asolvent.

6. A method of preparing 5,7-dihydroxy- (3,1,2)-oxadiazolo[4,5-dlpyrimidine which comprises mixing together2,4,6-trihydroxy-5-aminopyrimidine and nitrous acid in a solvent.

JAMES H. BOOTHE. COY W. WALLER.

No references cited.

1. CHEMICAL COMPOUNDS HAVING THE GENERAL FORMULA: